Zika Virus Disrupts Phospho-TBK1 Localization and Mitosis in Human Neuroepithelial Stem Cells and Radial Glia
Open accessAbstract
The mechanisms underlying Zika virus (ZIKV)-related microcephaly and other neurodevelopment defects remain poorly understood. Here, we describe the derivation and characterization, including single-cell RNA-seq, of neocortical and spinal cord neuroepithelial stem (NES) cells to model early human neurodevelopment and ZIKV-related neuropathogenesis. By analyzing human NES cells, organotypic fetal brain slices, and a ZIKV-infected micrencephalic brain, we show that ZIKV infects both neocortical and spinal NES cells as well as their fetal homolog, radial glial cells (RGCs), causing disrupted mitoses, supernumerary centrosomes, structural disorganization, and cell death. ZIKV infection of NES cells and RGCs causes centrosomal depletion and mitochondrial sequestration of phospho-TBK1 during mitosis. We also found that nucleoside analogs inhibit ZIKV replication in NES cells, protecting them from ZIKV-induced pTBK1 relocalization and cell death. We established a model system of human neural stem cells to reveal cellular and molecular mechanisms underlying neurodevelopmental defects associated with ZIKV infection and its potential treatment.
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The Zika virus is able to infect neuroepithelial stem cells and cortical radial glial cells and to a lesser extent postmigratory neurons, causing structural disorganization in these cells eventually leading to cell death.
“The Zika virus is able to infect neuroepithelial stem cells and cortical radial glial cells and to a lesser extent postmigratory neurons causing structural disorganization in these cells eventually leading to cell death [341–343].”
From Development of prefrontal cortex (2022) · cites this paper as [341]
The Introduction reports infection of neuroepithelial stem cells and radial glia, with less infection of postmigratory neurons, and links infection to structural disorganization and increased death of stem cells and radial glia. The Results section on NES-derived neurons reports no obvious increase in neuronal cell death, so the claim overextends those effects if “these cells” includes neurons. Page numbers are unavailable in our copy. (LLM, conf=0.88)
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References 68 · Cited by 292
- Authors
- Onorati, M., Li, Z., Liu, F., Sousa, A. M. M., Nakagawa, N., Li, M., Dell’Anno, M. T., Gulden, F. O., Pochareddy, S., Tebbenkamp, A. T. N., Han, W., Pletikos, M., Gao, T., Zhu, Y., Bichsel, C., Varela, L., Szigeti-Buck, K., Lisgo, S., Zhang, Y., Testen, A., Gao, X.-B., Mlakar, J., Popovic, M., Flamand, M., Strittmatter, S. M., Kaczmarek, L. K., Anton, E. S., Horvath, T. L., Lindenbach, B. D., & Sestan, N.
- Affiliations
- Yale University (US)
- University of North Carolina at Chapel Hill (US)
- Newcastle University (GB)
- University of Ljubljana (SI)
- Institut Pasteur (FR)
- Corresponding author
- Lindenbach, Brett D.
- ORCID
- Onorati, Marco
- Li, Zhen
- Liu, Fuchen
- Sousa, André M.M.
- Nakagawa, Naoki
- Li, Mingfeng
- Dell’Anno, Maria Teresa
- Gulden, Forrest O.
- Pochareddy, Sirisha
- Tebbenkamp, Andrew T.N.
- Pletikos, Mihovil
- Gao, Tianliuyun
- Zhu, Ying
- Varela, Luis
- Lisgo, Steven
- Zhang, Yalan
- Testen, Anze
- Gao, Xiao-Bing
- Mlakar, Jernej
- Flamand, Marie
- Strittmatter, Stephen M.
- Kaczmarek, Leonard K.
- Anton, E.S.
- Lindenbach, Brett D.
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2016-09
- Volume
- 16
- Issue
- 10
- Pages
- 2576-2592
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC5135012
- OpenAlex
- W2509505498
- Cited by
- 292
- References
- 68
- Citations by year
- 2026: 8 · 2025: 13 · 2024: 14 · 2023: 24 · 2022: 24 · 2021: 37 · 2020: 34 · 2019: 32 · 2018: 43 · 2017: 52 · 2016: 11
- FWCI
- 45.62
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion, cc-by-nc-nd)
- CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Newcastle University ePrints (Newcastle Univesity) (cc-by-nc-nd)
- Funders
- Wellcome Trust (099175/Z/12/Z)
- National Institutes of Health (UL1TR001863)
- Medical Research Council (MC_PC_15004)
- National Institute on Aging (P50AG047270, R01AG034924)
- National Institute of Mental Health (U01MH103339, R01MH060929, P50MH106934, U01MH105972)
- National Institute on Deafness and Other Communication Disorders (R01DC001919)
- National Institute of Allergy and Infectious Diseases (R21AI120113, R01AI089826)
- National Institute of Neurological Disorders and Stroke (R35NS097283, R01NS076503, R01NS080388)
- National Center for Advancing Translational Sciences
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (Z01HD008836)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Mosquito-borne diseases and control
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Health Sciences › Medicine › Epidemiology › Virology and Viral Diseases
- Keywords
- Zika virus, microcephaly, neuroepithelial stem cells, radial glia, mitosis, TBK1 phosphorylation, supernumerary centrosomes, neurodevelopmental defects, nucleoside analogues, viral replication inhibition, cell death, organotypic brain slices
- MeSH terms
- Zika Virus Infection, Zika Virus, Axl Receptor Tyrosine Kinase, Brain, Fetus, Humans, Immunity, Innate, Microcephaly, Mitochondria, Mitosis, Neuroglia, Neurons, Nucleosides, Phosphorylation, Proto-Oncogene Proteins, Spinal Cord, Transcription, Genetic, Virus Replication, Cell Death, Protein Serine-Threonine Kinases, Centrosome, Neuroprotective Agents, Neocortex, Receptor Protein-Tyrosine Kinases, Gene Expression Profiling, Neuroepithelial Cells, Protein Kinase Inhibitors, Neural Stem Cells
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